Apremilast is a phosphodiesterase 4 (PDE4) inhibitor indicated for the treatment of (1) adult patients with active psoriatic arthritis, and (2) patients with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy.
In U.S. Pat. No. 6,962,940 B2, Muller et al. disclosed that apremilast was produced by heating (S)-1-(3-ethoxy-4-methoxyphenyl)-2-(methylsulfonyl)ethanamine N-Ac-L-Leucine salt 1 with 3-acetamidophthalic anhydride 2 in HOAc (acetic acid) at reflux temperature (˜118° C.) overnight (Scheme 1).

Most of the HOAc was removed by distillation under reduced pressure, and EtOAc was added to the concentrate achieving a homogeneous solution. The solution was successively washed with H2O (twice), saturated NaHCO3(aq) (twice), saturated NaCl(aq) (twice) and then dried over Na2SO4. The mixture was filtered, and most of EtOAc was removed by distillation under reduced pressure affording crude apremilast. After recrystallization from a mixture of acetone/EtOH, purified apremilast was obtained in 75% yield with 98% ee. Information of purity and the polymorph for the resulting apremilast was not reported.
A closely related example was disclosed in US 20140081032 A1 where d3-(S)-aminosulfone N-Ac-L-Leucine salt d3-1 was first neutralized to give its corresponding d3-(S)-aminosulfone without further purification. The d3-(S)-aminosulfone was used directly for apremilast formation (Scheme 2).

A mixture containing d3-(S)-aminosulfone and 3-acetamidophthalic anhydride 2 was heated in a mixture of HOAc/THF at reflux temperature (˜70° C.) for 24 hr. The mixture was diluted with THF and IPAc after reaction completion. The resulting mixture was sequentially washed with 10% NaH2PO4(aq) (three times) and H2O (three times). The washed mixture was concentrated under reduced pressure affording crude d3-apremilast. After successive recrystallization from a mixture of IPAc/MTBE and a mixture of acetone/EtOH, purified d3-apremilast was obtained in 79% yield with 99.9% purity and 99.0% ee. Information regarding the polymorph for the resulting apremilast was not available.
In U.S. Pat. Nos. 7,893,101 B2 and 8,093,283 B2, Celgene Corporation disclosed several polymorphs of apremilast including Forms A, B, C, D, E, F and G.